Cancer stem cells (CSCs) are critical drivers of tumor progression and recurrence. Therefore, CSC eradication is crucial for achieving durable remission. However, the molecular pathways leading to CSC induction and accumulation remain poorly understood. We hypothesize that CSCs accumulate due to their inability to give rise to terminally differentiated cells. Our unpublished data demonstrate that under stress conditions, intestinal stem cells (ISCs) differentiate into various lineages of the gut epithelium, potentially as a mechanism to maintain stem cell pool integrity. Our observations suggest that differentiation processes are prioritized to preserve barrier function in tissues required to maintain barrier integrity. We are examining the ability of ISCs to differentiate under stress as a mechanism to ensure the integrity of the stem cell pool. We employ single-cell genomics, transgenic mouse models, and high-resolution imaging techniques to explore the capacity of stem cells to differentiate following DNA damage and eliminate cells with high mutational burden. Furthermore, we aim to demonstrate that the appearance of driver mutations in CRC blocks this differentiation process. This research will advance our understanding of stem cell protective mechanisms that preserve a healthy stem cell pool and prevent cancer initiation. By elucidating these processes, we may identify novel therapeutic targets for cancer prevention and treatment, particularly colorectal cancer.
1. Lineage tracing of intestinal stem cells under irradiation stress. Scheme of the experimental plan (top panel). Image of intestinal crypts in high magnification, showing the labeling of intestinal stem cells with tdTomato upon induction of Tamoxifen for 24h. This system will allow us to follow stem cell differentiation under normal or irradiation stress.